[Federal Register Volume 62, Number 43 (Wednesday, March 5, 1997)]
[Notices]
[Pages 10050-10053]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-4879]


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ENVIRONMENTAL PROTECTION AGENCY
[PF-700; FRL-5586-1]


Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of filing.

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SUMMARY: This notice announces the filing of a pesticide petition 
proposing to establish tolerances for residues of thiodicarb and its 
metabolite in or on leafy vegetables, broccoli, cabbage and 
cauliflower. The notice includes a summary of the petition prepared by 
the petitioner, Rhone-Poulenc Ag Company.

DATES: Comments, identified by the docket control number [PF-700], must 
be received on or before, April 4, 1997.

ADDRESSES: By mail, submit written comments to: Public Response and 
Program Resources Branch, Field Operations Division (7506C), Office of 
Pesticide Programs, Environmental Protection Agency, 401 M St. SW., 
Washington, DC 20460. In person, bring comments to: Rm. 1132, Crystal 
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202.
    Comments and data may also be submitted electronically by sending 
electronic mail (e-mail) to: [email protected]. Electronic 
comments must be submitted either as an ASCII file avoiding the use of 
special characters and any form of encryption. Comments and data will 
also be acceped on disks in Wordperfect in 5.1 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket control number [PF-700]. Electronic comments 
on this notice may be filed online at many Federal Depository 
Libraries. Additional information on electronic submissions can be 
found below this document.
    Information submitted as a comment concerning this notice may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). Information so marked will 
not be disclosed except in accordance with procedures set forth in 40 
CFR Part 2. No CBI should be submitted through e-mail. A copy of the 
comment that does not contain CBI must be submitted for inclusion in 
the public record.

[[Page 10051]]

Information not marked confidential may be disclosed publicly by EPA 
without prior notice.

FOR FURTHER INFORMATION CONTACT: Dennis H. Edwards, Jr. Product Manager 
(PM 19), Registration Division, (7505C), Office of Pesticide Programs, 
Environmental Protection Agency, 401 M St., SW., Washington, DC. Office 
location, telephone number and e-mail address: Rm., 207, Crystal Mall 
#2, 1921 Jefferson Davis Highway, Arlington, VA.; Telephone: 703-305-
6386, e-mail: [email protected].

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions (PP) 
6F3417 and 7F3516 from Rhone-Poulenc Ag Company, P.O. Box 12014, 2 T.W. 
Alexander Drive, Research Triangle Park, NC 27709. These petitions 
propose, pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act (FFDCA), 21 U.S.C. section 346a, to amend 40 CFR part 180 
by establishing tolerances for the combined residues of the insecticide 
thiodicarb (Dimethyl N,N-[thiobis[[(methylimino) carbonyl]oxy]] bis 
[ethanimidothioate]) and its metabolite methomyl (S-methyl N 
[(methylcarbamoyl)oxy]-thioacetimadate) in or on the following raw 
agricultural commodities: leafy vegetables at 35 parts per million 
(ppm), broccoli at 7 ppm, cabbage at 7 ppm, and cauliflower at 7 ppm. 
The proposed analytical method is HPLC.
    As required by section 408(d) of the FFDCA, as recently amended by 
the Food Quality Protection Act (FQPA), Rhone-Poulenc Ag Company 
included in the petition a summary of the petitions and authorization 
for the summary to be published in the Federal Register in a notice of 
receipt of the petition. The summary represents the views of Rhone-
Poulenc Ag Company; EPA is in the process of evaluating the petition. 
As required by section 408(d)(3), EPA is including the summary as a 
part of this notice of filing. EPA may have made minor edits to the 
summary for the purpose of clarity.

I. Petition Summary

A. Residue Chemistry

    The metabolism of thiodicarb in plants and animals is adequately 
understood. Adequate analytical methods are available for enforcement 
purposes. There are no livestock feed items associated with this 
petition; there are no problems of secondary residues in meat, milk, 
poultry or eggs.

B. Toxicological Profile

    1. Acute toxicity. EPA evaluation of the three acute oral toxicity 
studies in rats indicated the LD50 in males and females to be >50 
miligrams/kilograms (mg/kg). Based on the results of these studies, 
thiodicarb is placed in Toxicity Category II. The acute dermal toxicity 
study in rabbits resulted in a LD50 of >2,000 mg/kg for both males 
and females. The acute inhalation LC50 was found to be >0.56 mg/l 
in male and female rats. The primary eye irritation study showed iridal 
involvement and moderate to severe conjunctival irritation. All 
positive reactions cleared within 4 days and eyes had returned to a 
normal appearance by day 7 following treatment. There was no irritation 
in the primary dermal irritation study. Thiodicarb was a weak dermal 
sensitizer in guinea pigs.
    Conclusion. Based on the acute toxicity data cited above, Rhone-
Poulenc Ag Company concludes that thiodicarb does not pose any acute 
dietary risks.

    2. Mutagenicity. Mutagenicity studies completed include Salmonella 
typhimurium mammalian microsome reverse mutation assay (negative), 
Saccharomyces cerevisiae reverse mutation (negative), mitotic crossing 
over (negative) and gene conversion (positive in strain D7 and negative 
in strain D4), primary DNA damage in Escherichia coli (negative), mouse 
lymphoma gene mutation assay (equivocal positive), chromosomal 
aberration assay in CHO cells (negative), UDS assay with primary rat 
hepatocytes (negative), in vivo micronucleus test in mouse bone marrow 
(negative) and dominant lethal test in rats (negative).
    Conclusion. Thiodicarb was tested in a variety of mutagenicity 
assays and was negative in all but the mouse lymphoma assay, in which 
there was only a weak to equivocal response and for mitotic gene 
conversion in Saccharomyces cerevisiae. EPA has previously concluded 
that overall there is low concern for the mutagenicity of thiodicarb.

    3. Metabolism. The metabolism of thiodicarb has been studied in 
several animal and plant species and studies submitted and accepted by 
EPA. The metabolism in plants and animals is adequately understood for 
the purposes of this tolerance.
    4. Chronic effect. Based on the available chronic toxicity data, 
the Health Effects Division-RfD/Peer Review Committee of the EPA 
recommended in their RfD/Peer Review Report (Ghali, June 18, 1996) that 
the Reference Dose (RfD) for thiodicarb remain unchanged from the 
previously established value of 0.03 mg/kg/day. The recently completed 
rat studies support the no observed effect level (NOEL) of 3 mg/kg/day 
established in previous studies. An Uncertainty Factor (UF) of 100 was 
applied to account for both the interspecies extrapolation and 
intraspecies variability.
    5. Carcinogenicity. The potential oncogenicity of thiodicarb has 
been fully evaluated by the EPA's Health Effects Division 
Carcinogenicity Peer Review Committee (CPRC) (Taylor and Rinde, June 
10, 1996). The committee determined that the available database was 
adequate for the determination of the carcinogenicity of thiodicarb in 
animals and concluded that thiodicarb should be classified in Group B2. 
While Rhone-Poulenc disagrees with the classification of thiodicarb and 
the interpretation of the study results (as described below) Rhone-
Poulenc agrees with the risk characterization procedure recommended by 
the CPRC and concurs that the recommended procedures are fully adequate 
to protect humans from dietary exposure to thiodicarb.
    The CPRC recommended that a margin of exposure methodology be 
applied for the estimation of human risk because the findings observed 
in the oncogenicity studies occurred only at the highest doses tested 
in the studies and in the case of mice the highest dose tested may even 
have been excessive. In addition, there was no evidence of 
genotoxicity.
    a. Rhone-Poulenc feels that the results in the most recent 
oncogenicity study in rats should not be considered indicative of a 
carcinogenic response in the Leydig cells of the rats for the following 
reasons:
    i.  Compared to the control groups, both sexes at the high dose 
level displayed fewer tumors and there were fewer with multiple benign 
and malignant tumors.
    ii.  There was a statistically significant decrease in pituitary 
adenomas in the high dose animals relative to controls (10 percent vs 
56 percent ) indicating more high dose than control animals had normal 
pituitaries at the end of the study. The incidence of pituitary 
adenomas is well below the historical control range (10 percent vs a 
range of 43 to 80 percent ). Pituitary activity is known to be critical 
in the regulation of benign Leydig cell tumor formation through the 
secretion of luteinizing hormone. Increased pituitary activity in aged 
male rats would be expected to secondarily result in increased benign 
Leydig cell tumor formation.
    iii.  There was no statistical increase in benign interstitial cell 
tumors relative to the concurrent controls when all

[[Page 10052]]

animals were included in the statistical analysis.
    iv.  There is clear evidence that exposure to 900 ppm thiodicarb 
resulted in increased survival for male rats relative to controls. The 
2 year survival rate for high dose males was 1.3 times that of controls 
(58 percent vs 45 percent, respectively). Benign interstitial cell 
tumors are very common age related tumors. Because survival was 1.3 
times higher in the high dose group than in controls, the high dose 
animals should be expected to have a higher raw incidence of common age 
related tumors.
    v.  Benign interstitial cell tumors do not transform into a more 
aggressive form with time.
    vi.  Benign interstitial cell tumors are very common in rats and 
highly uncommon in humans. There is an absence of epidemiological 
evidence that Leydig cell tumors in rats are relevant for human health 
risk assessment. The Food and Drug Administration (FDA), and European 
regulatory authorities in general do not consider these findings to be 
relevant for human health risk assessment. Numerous scientific 
symposia/discussions have been held regarding the lack of relevance of 
rat Leydig cell changes for human risk assessment.
    b. Rhone-Poulenc feels that the results in the most recent mouse 
oncogenicity study should not be considered indicative of a 
carcinogenic response in the liver cells of the mice for the following 
reasons:
    i.  The evidence shows that thiodicarb is not oncogenic in mice at 
doses which do not exceed the maximum tolerated dose (MTD).
    ii.  There was no evidence to suggest liver oncogenicity in the 
first mouse study at doses up to 10 mg/kg/day or in the second study at 
doses up to 70 mg/kg/day.
    iii.  In the second study where there was evidence suggestive of an 
oncogenic response in the liver, the MTD was significantly exceeded 
based on increased mortality in females and a dramatic body weight gain 
depression in the males. The body weight gains for males at 1,000 mg/
kg/day were 54 percent of the control male gains during the first year 
of the study. The body weight gains for the 1,000 mg/kg/day group 
females were 85 percent of controls for the same time period. 
Survivability at 97 weeks was also significantly decreased in males (41 
percent versus 58 percent in control males) and females (24 percent 
versus 51 percent in control females).
    iv.   Other evidence that the MTD was exceeded included severe and 
sustained liver toxicity demonstrated by increased liver weights, 
hepatocyte hypertrophy, single cell necrosis and hemosiderin deposition 
by 52 weeks and increased bilirubin and ALT, increased liver weight, 
hepatocyte hypertrophy, bile duct hyperplasia, hepatocyte pleomorphism 
and hemosiderin deposition at 97 weeks of treatment.
    Conclusion. The oncogenicity studies with thiodicarb fully conform 
to the currently accepted guidelines for this study type. Rhone-Poulenc 
Ag Company believes that the results of the studies provide only 
minimal evidence that the compound is oncogenic in rodents. After 
analysis of the data, EPA scientists recently determined that a margin 
of exposure of 100 applied to the lowest NOEL from the chronic studies 
with thiodicarb would provide adequate safety for any risks to humans. 
Rhone-Poulenc agrees with this risk assessment approach and is 
confident that it will provide adequate safety for all human population 
subgroups including infants and children.

    6. Teratology. Several teratology studies exist on thiodicarb in 
rats, rabbits, and mice. These are reviewed below:
    a. A teratology study in rats was conducted at doses of 0, 0.5, 
1.0, 3, and 100 mg/kg/day. No signs of teratogenicity were observed.
    b. A teratology study was conducted in rats at doses of 0, 1, 10 
and 30 mg/kg/day. No signs of teratogenicity were observed.
    Data from both studies can be (and were by EPA) used to derive 
maternal and developmental NOELs and lowest observed effect levels 
(LOELs). Based on data from both studies, the maternal NOEL and LOEL 
were determined to be 10 and 20 mg/kg/day, respectively. The 
developmental NOEL and LOEL were determined to be 3 and 10 mg/kg/day, 
respectively, based on delayed ossification of sternebrae.
    c. A teratology study in rabbits was conducted at doses of 0, 5, 20 
and 40 mg/kg/day. No signs of teratogenicity were observed. The NOEL 
and LOEL for maternal toxicity were determined to be 20 and 40 mg/kg/
day, respectively. The developmental NOEL was determined to be 40 mg/
kg/day. As this was the highest level tested, no LOEL for developmental 
toxicity was determined.
    d. A teratology study in mice was conducted at doses of 0, 50, 100 
and 200 mg/kg/day. No signs of teratogenicity were observed. The 
maternal NOEL and LOEL were determined to be 100 and 200 mg/kg/day, 
respectively. As no fetal effects were observed at all, the 
developmental NOEL can be considered to be 200 mg/kg/day.
    Conclusion. Based on all the studies above, Rhone-Poulenc Ag 
Company does not believe that thiodicarb is a teratogen, or that it 
presents any unreasonable risk to children.

    7. Reproductive effects. Two reproduction studies were recently 
conducted with thiodicarb; one dose-rangefinding study and one 
definitive study.
    a. In the dose-rangefinding study, rats were administered 
thiodicarb in their diets at concentrations of 0, 200, 600, 1,800, and 
3,000 ppm. Maternal toxicity, as evidenced by decreased pup viability 
at birth and day 4, was seen at the three highest doses. Also at the 
three highest doses, decreased pup growth occurred. Therefore, the NOEL 
for both maternal and fetal effects was determined to be 200 ppm.
    b. In the definitive study, thiodicarb was administered in the 
diets of rats at concentrations of 0, 100, 300, and 900 ppm. Fetal body 
weight gain at 100 ppm was significantly decreased when compared with 
concurrent controls resulting in the conclusion that, strictly 
speaking, no NOEL was reached for fetal effects in this study. An 
independent expert consulting firm was contracted with to statistically 
derive from these data a conservative NOEL for all effects. These 
experts concluded that a conservative NOEL for all effects would be 80 
ppm, equivalent to an average daily dose of 5.20 mg/kg/day. EPA 
subsequently utilized a Benchmark Dose approach to estimate the NOEL 
for this study, and ultimately concluded that, based on all the data 
and all the different analyses of the data, 100 ppm is at or near the 
NOEL for reproductive/developmental toxicity. It is significant, too, 
that this NOEL is higher than the NOEL from the chronic toxicity/
oncogenicity study in rats, where the NOEL is used to determine the 
Reference Dose for thiodicarb.
    Conclusion. Based on the studies cited above, Rhone-Poulenc Ag 
Company believes that thiodicarb does not pose an unreasonable risk of 
reproductive effects to parents or their offspring. Further, as none of 
the effects observed in the cited studies are classically related to 
any specific endocrine mechanism, Rhone-Poulenc Ag Company believes 
that thiodicarb is not an endocrine disrupter.

C. Aggregate Exposure/Cumulative Effects

    The Dietary Analysis for the Proposed Use of thiodicarb on leafy 
vegetables has been run by EPA and summarized in a document dated June 
17, 1991 (Schaible, S.A.). Using the Theoretical

[[Page 10053]]

Maximum Residue Contributions (TMRC) calculated from the tolerances and 
estimated consumption data for various populations (very conservative 
estimates) a value of 0.019213 is obtained for the TMRC which 
represents 64.0 percent of the established reference dose was reached 
for the overall U.S. population. The Dietary Analysis for the Proposed 
Use of thiodicarb on broccoli, cabbage and cauliflower has been run by 
EPA and summarized in a document dated July 9, 1990 (Briggs, R.). Using 
the TMRC calculated from the tolerances and estimated consumption data 
for various populations (very conservative estimates). A value of 
0.015225 is obtained for the TMRC which represents 50.8 percent of the 
established reference dose utilized for the overall U.S. population. 
None of the population subgroups exceeded the 100 percent level of the 
reference dose. This value includes all pending and published 
tolerances, including apples, tomatoes and peppers for which Rhone-
Poulenc Ag Company does not currently have a registration. This is a 
large overestimation of the actual dietary exposure to thiodicarb 
because it assumes 100 percent of crops treated and maximum residue 
levels present.
    The FQPA of 1996 lists three other potential sources of exposure to 
the general population that must be addressed, these are pesticides in 
drinking water, exposure from non-occupational sources, and the 
potential cumulative effect of pesticides with similar toxicological 
modes of action. Based on the available studies of thiodicarb in the 
environment which show a short half-life in soil (1.5 days), Rhone-
Poulenc Ag Company does not anticipate residues of thiodicarb in 
drinking water. There is no established Maximum Concentration Level or 
Health Advisory Level for thiodicarb under the Safe Drinking Water Act.
    The potential for non-occupational exposure to the general public 
is also insignificant. There are no residential lawn or garden uses for 
thiodicarb products where the general population may be exposed via 
inhalation or dermal routes.
    Rhone-Poulenc concludes that consideration of a common mechanism of 
toxicity is not appropriate at this time since there is no reliable 
data to indicate that the toxic effects caused by thiodicarb would be 
cumulative with those of any other compound. Based on this point, 
Rhone-Poulenc has considered only the potential risks of thiodicarb in 
it's exposure assessment.

D. Safety Determinations

    1. U.S. population in general. Using the very conservative exposure 
estimates described above, the conclusion reached is that aggregate 
exposure to thiodicarb will utilize no more than 64 percent of the 
established reference dose. Rhone-Poulenc Ag Company has conducted a 
preliminary Dietary Risk Exposure Study (DRES) with TAS, Inc. which 
utilizes actual data (where available) for percent crops treated and 
residue data from FDA and Cal-EPA monitoring programs (no detectable 
residues of thiodicarb were observed in these databases, so as a 
conservative estimate, all methomyl residues were assumed to result 
from thiodicarb use). Only registered and conditionally registered uses 
(including leafy vegetables, broccoli, cabbage and cauliflower) were 
included in the analysis. The study concluded that chronic exposure 
estimates are well below the endpoints of concern. Chronic exposure 
estimates are 0.1 percent of the RfD or less for all population groups. 
Based on this study and the above points, Rhone-Poulenc Ag Company 
believes there is a reasonable certainty that no harm will result from 
aggregate exposure to thiodicarb.
    2. Infants and children. Referring to the conclusions and summary 
in the Developmental and Reproductive Toxicity section stated above, 
Rhone-Poulenc Ag Company believes there is no additional sensitivity 
for infants and children and that an additional safety factor for 
infants and children is not warranted. The RfD of 0.03 mg/kg/day is 
appropriate for assessing aggregate risk to this subpopulation. For the 
infant and children (1 to 6 years of age) populations only 0.1 percent 
of the reference dose was used in the DRES study discussed above.
    Based on the completeness and reliability of the toxicology data 
and the dietary analysis Rhone-Poulenc Ag Company concludes that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to thiodicarb residues.

E. International Tolerances

    There are no Codex maximum residue levels established for 
thiodicarb on leafy vegetables, broccoli, cabbage or cauliflower.

II. Public Record

    EPA invites interested persons to submit comments on this notice of 
filing. Comments must bear a notification indicating the docket control 
number [PF-700].
    A record has been established for this notice under docket control 
number [PF-700] (including comments and data submitted electronically 
as described below). A public version of this record, including printed 
paper versions of electronic comments, which does not include any 
information claimed as CBI, is available for inspection from 8:30 a.m. 
to 4 p.m., Monday through Friday, excluding legal holidays. The public 
record is located in Rm. 1132 of the Public Response and Program 
Resources Branch, Field Operations Division (7506C), Office of 
Pesticide Programs, Environmental Protection Agency, Crystal Mall #2, 
1921 Jefferson Davis Highway, Arlington, VA.
    Electronic comments can be sent directly to EPA at:
    [email protected]


    Electronic comments must be submitted as ASCII file avoiding the 
use of special characters and any form of encryption.
    The official record for this notice, as well as the public version, 
as described above will be kept in paper form. Accordingly, EPA will 
transfer all comments received electronically into printed, paper form 
as they are received and will place the paper copies in the official 
notice record which will also include all comments submitted directly 
in writing. The official notice record is the paper record maintained 
at the address in ``ADDRESSES'' at the beginning of this document.

    Authority: 21 U.S.C. 346a.

List of Subjects

    Environmental Protection, Administrative practice and procedure, 
Agricultural commodities, Pesticide and pest, Reporting and 
recordkeeping requirements.

    Dated: February 10, 1997.

Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.

[FR Doc. 97-4879 Filed 3-4-97; 8:45 am]
BILLING CODE 6560-50-F